1-(4-PHENYL-1-PIPERIZINYL METHYL)-CYCLOPROPA{8 a{9 NAPHTHALENES AND CYCLOPROP{8 a{9 INDENES

ABSTRACT

Cis and trans-1-(nitrogenheterocyclylmethyl)cyclopropa(a)naphthalenes and 1-(nitrogenheterocyclylmethyl)cycloprop(a)indenes useful as antiinflammatory agents are disclosed. The trans isomers are prepared by reacting 1,1a,6,6a-tetrahydro-1H-cycloprop(a)indenecarbonyl chloride and 1a,2,3,7b-tetrahydro-1Hcyclopropa(a)naphthalenecarbonyl chloride with a nitrogencontaining heterocyclic compound and reducing the amide with lithium aluminum hydride to give the reduced compounds. The cis isomers are prepared by reacting equimolar amounts of cis-1,1a, 6,6a-tetrahydro-1H-cycloprop(a)indenecarboxylic acid and cis-1a, 2,3,7b-tetrahydro-1H-cyclopropa(a)naphthalenecarboxylic acid, a nitrogen-heterocyclic compound and dicyclohexylcarbodiimide and reducing the amides obtained thereby.

United States Patent [151 3,666,761 Welstead, Jr. 1 May 30, 1972 541 1-(4-PHENYL-l-PIPERIZINYL 3,098,076 7/1963 Baltzly ..260/469X METHYL)-CYCLOPROPA[A] 3,419,604 12/1968 Kaiser etal. ..260/268X $5 ENES AND CYCLOPROP[A] Primary Examiner-Donald G. Daus Att0meyG. William King and Norman D. Dawson [72] Inventor: William John Welstead, Jr., Richmond,

Va. [57] ABSTRACT [73] Assignee: A. H. Robins Company, Incorporated, Cis and trans-1-(nitrogen-heterocyclylmethyl)cyclopropa[ Richmond, Va.

Filed: July 16, 1969 Appl. No; 842,354

References Cited UNITED STATES PATENTS l 1/1961 Kaiser et al. ..260/469 X a]naphthalenes and l-( nitrogen-heterocyclylmethyl)cycloprop[a]indenes useful as anti-inflammatory agents are disclosed. The trans isomers are prepared by reacting 1 ,1a,6,6a-tetrahydro-lH-cycloprop[a]indenecarbonyl chloride and la,2,3 ,7b-tetrahydrol H-cyclopropal a ]n aphthalenecarbonyl chloride with a nitrogen-containing heterocyclic compound and reducing the amide with lithium aluminum hydride to give the reduced compounds. The cis isomers are prepared by reacting equimolar amounts of cisl l a,6,6a-tetrahydroi H-cycloprop[ alindenecarboxylic acid and cisl a,2,3 ,7b-tetrahydrol H-cyclopropa[ a]n aphthalenecarboxylic acid, a nitrogen-heterocyclic compound and dicyclohexylcarbodiimide and reducing the amides obtained thereby.

6CIaims,No Drawings 1 -(4-PHENYL- 1 -PIPERIZINYL METHYL)- CYCLQPROPMAm-CLOPROPI I CHz-SUB V 7 (C391. Formula I wherein;

SUB is a heterocyclic radical selected from 4-phenylpiperidinyl, 4-benzylpiperidinyl, 4-phenylpiperazinyl, 4-phenyl-l ,2,3,-tetrahydropyridinyl, 3-phenylpyrrolidinyl and 3- phenyl-3-pyrrolinyl, wherein said phenyl is unsubstituted phenyl and monosubstituted phenyl, wherein the monosubstituent is selected from lower alkyl, lower alkoxy, trifluoromethyl and halogen of atomic weight less than eighty,

n is a positive integer from 1 to 2 inclusive, and non-toxic acid addition salts thereof.

The present invention resides in the linkage of the heterocyclic moieties to the cyclopropa[a]naphthalenes and cycloprop [a]indenes by a methylene group, the novel compounds resulting therefrom possessing useful pharmacological activity. The pharmacological action of the novel compounds of the present invention resides in their ameliorating effects on inflamed cellular sites. The activity is demonstrated when the compounds are used in the form of the free base or in the form of their non-toxic acid addition salts. The preferred form of the compounds is as their non-toxic acid addition salts for increased water solubility and ease of administration.

As described hereinabove, the novel compounds of the present invention have an ameliorating effect against inflamed cellular sites and are therefore useful as anti-inflammatory agents. In particular, among the novel compounds of the present invention which have been shown to possess anti-inflammatory action, the compounds of Examples 1 and 6, namely, transl 4-phenyll-piperazinylmethyl)- l a,2,3 ,7btetrahydro-lI-I-cyclopropa[a]naphthalene and trans-l-[4-(4- anisyl l-piperazinylmethyl]- l a,2,3 ,7b-tetrahydrol H- cyclopropa[a]naphthalene hydrochloride are preferred. The anti-inflammatory action was demonstrated using a modified method of carrageenin-induced edema in the hind paw of the rat (C. A. Winder et al., Proc. Soc. Exp. Biol. Med. III, 544, 1962). Inflammatory edema resulting from the injection of carrageenin in the rat paw was significantly inhibited when the compounds of Examples 1 and 6 were administered orally at doses of 10 to 100 mg./kg., the preferred dose being to 40 mg./kg. The compound of Example 1 was also tested and compared with known antiphlogistic agents in rats using a modified method of the granuloma pouch test (A. Robert and J. E. Nezamis, Acta. Endocrinologia, 25, 105, 1957); there was a marked decrease in the weight of pouch exudate at an oral dose of about 20-60 mgJkg. A preferred oral dose was 30 to 40 mg./kg.

It is, therefore, an object of the present invention to provide novel l-(nitrogen-heterocyclylmethyl)cyclopropa[a] naphthalenes and l-(nitrogen-heterocyclylmethyl)cycloprop[ a]indenes having utility as anti-inflammatory agents. Another object is to provide methods for producing the novel compounds, therapeutic compositions containing the same and methods for the utilization thereof. Other objects of this invention will be apparent to one skilled in the art and still other objects will become apparent hereinafter.

In the definition of symbols in the foregoing Formula I and where they appear elsewhere throughout this specification, the terms have the following significance.

The term lower-alkyl" as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, amyl, hexyl, octyl, and the like. Lower-alkoxy"has the formula -O-lower alkyl.

When halogen is referred to herein, preferably but not necessarily a halogen of atomic weight less than eighty is employed. Of the halogens, chlorine is preferred.

By phenyl is meant the unsubstituted and the monosubstituted phenyl radical. Among the suitable substituted phenyl radicals are phenyl radicals substituted by any radical which is not reactive or otherwise interfering under the conditions of reaction such as lower-alkoxy, lower-alkyl, trifluoromethyl, and halo. The lower-alkyl and lower-alkoxy substituents have preferably from one to four carbon atoms which can be arranged as straight or branched chains.

The compounds of Formula I'may be converted to and are most conveniently employed in the form of non-toxic pharmaceutically acceptable acid addition salts. Such salts also have improved water solubility. Although the non-toxic salts are preferred, any salt may be prepared for use as a chemical intermediate, as in the preparation of another but non-toxic acid addition salt. The free basic compounds of Formula I may be conveniently converted to their acid addition salts by reaction of the free base with the selected acid, preferably in the presence of an organic solvent inert to the reactants and reaction products under the conditions of the reaction. The acids which can be used to prepare the preferred non-toxic acid addition salts are those which produce, when combined with the free base, salts, the anions of which are relatively innocuous to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties inherent in the free bases are not vitiated by side effects ascribable to the anions.

Appropriate acid addition salts are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid, and phosphoric acid, and organic acids such as maleic acid, oxalic acid, lactic acid, fumaric acid, and tartaric acid. The preferred acid addition salt is the hydrochloride.

The acid addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and the selected acid in an organic solvent, in which case the salt ordinarily separates directly or can be conventionally recovered by concentration of the solution or the like. Conversely, the free base may be obtained conventionally by neutralizing the acid addition salt with an appropriate base such as ammonia, ammonium hydroxide, sodium carbonate or the like, extracting the liberated base with a suitable solvent, illustratively ethyl acetate or benzene, drying the extract and evaporating to dryness or fractionally distilling or in other conventional manner.

The starting materials used in preparing the novel compounds are ethyl l,la,6,6a-tetrahydro-lH-cycloprop[a]i ndenecarboxylate and ethyl la,2,3,7b-tetrahydrol H- cyclopropa{a]naphthalene-carboxylate which are prepared by modified methods described in US. Pat. No. 3,010,972 and in Chem. Ber. 94, 2332 (1962). An excess of indene or naphthalene is reacted with ethyl diazoacetate in the presence of a catalyst such as copper sulfate or copper cyanide. The resulting ester is purified, usually by distillation in vacuo. Saponification of the ester yields the corresponding acid which is isolated by acidifying the basic hydrolysate and collecting the resulting precipitate. Following recrystallization from ethanol-water, the isomeric mixture of carboxylic acids is dissolved in a dilute basic solution and partially neutralized with hydrochloric acid to obtain primarily the crude trans isomer which is further purified by crystallization. Complete neutralization of the basic solution precipitates the crude cis isomer which is purified by repeated crystallization from a suitable solvent.

The novel compounds of the present invention are prepared as shown in Chart l.

CHART I 5 S001: i i COOH 11-61 \/\(CH2)R 2)n II (cis or trans) III (trans) II (sis) SUB and i l S UB DCCD i O 15 SUB ii-SUB lCHfl" ((311 IV trans) Y ii i iini 1 intuit l (cis) I (trans) DCCD is dicyclohexylcarbodiimide.

SUB is nitrogen heterocyclic radical.

The trans-isomers of the novel compounds are prepared by treating 1', l a,6,6a-tetrahydrol H-cycloprop[a]indenecarboxylic acid (11 or la,2,3,7b-tetrahydro-1H-cyclopropa[a]n aphthalene-carboxylic acid (11) with phosphorous trichloride, phosphorous pentachloride or thionyl chloride, thionyl chloride being preferred, to give the acid chloride ([11). The acid chloride (III) is reacted with a nitrogen-containing heterocyclic compound to give the amides of Formula 1V. The

latter reaction is generally carried out in a suitable inert organic solvent such as benzene, chloroform, dioxane, toluene, acetonitrile and the like. An acid acceptor such as a tertiary amine or an alkali metal salt of a weak acid, such as sodium carbonate, sodium bicarbonate, potassium carbonate and the like, may be used, an alkali metal salt being preferred. Alternatively, the reaction described above can be conveniently carried out in a chloroform-water mixture. The alternate method is particularly convenient when the acid acceptor employed is an alkali metal salt of a weak acid. The reaction is generally carried out at or about room temperature for a period of from about 2 to 4 hours. Isolation of the amide (IV) is achieved by dilution of the reaction mixture with water, separation of the organic and aqueous layers, and drying and concentration of the organic layer. The crude products are purified by crystallization from a suitable solvent such as benzene, isopropyl ether, benzene-isooctane, and the like.

When either cis-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]n aphthalenecarboxylic acid or cis-l,1a,6,6a-tetrahydro-1H- cycloprop[a]indenecarboxylic acid is treated with thionyl chloride, it is epimerized to the corresponding trans-isomer. Therefore, in preparing novel compounds of the invention having the cisconfiguration, cis-la,2,3,7b-tetrahydro-IH- cyclopropala]naphthalenecarboxylic acid (H) or cisl,la,6,6a-tetrahydro-lH-cycloprop [a]indenecarboxylic acid (ll) is reacted with approximately equimolar amounts of a nitrogen-containing heterocyclic compound and dicyclohexylcarbodiimide (DCCD) in an inert solvent such as methylene chloride. The reaction is generally carried out at or about room temperature for a period of from about 3 to 5 hours. The crude amide is usually isolated by filtering ofi the insoluble solids and acid-base extraction of the filtrate. The organic layer is dried and concentrated to an oil and the residual crude amide is purified by crystallization.

The reduction of the precursor amides (IV) to the novel 1 (nitrogen-heterocyclylmethyl l 1a,6,6atetrahydro-1H- cycloprop[a]indenes (l) and l-(nitrogen-heterocyclylmethyl 1a,2,3 ,7b-tetrahydro- 1 H-cyclopropa[ a]naphthalenes (1) of the present invention is achieved by alkali metal hydride reduction in anhydrous ether. The amide is dissolved or suspended in ether and added dropwise, under nitrogen, to a stirred suspension of lithium aluminum hydride in ether. The stirred reaction mixture is refluxed for a period of from about 2 to 5 hours. The excess lithium aluminum hydride is decomposed by the addition of water and the organic layer is separated and concentrated in vacuo. The crude residual basic material is purified by crystallization or it is converted to an organic or inorganic acid addition salt which is further purified by crystallization from a suitable solvent.

Preparation 1 Cis and trans-l,1a,6,6a-tetrahydro-1H-cycloprop[a]i ndenecarboxylic Acid.

a. To a stirred solution of 38 g. (0.19 mole) of ethyl- 1 1a,6,6atetrahydrol H-cycloprop[a lindenecarboxyl ate and 200 ml. of ethanol was added 25 g. (0.62 mole) of sodium hydroxide in 40 ml. of water. The reaction mixture was refluxed under nitrogen for 6 hours. The cooled hydrolysate was acidified with dilute hydrochloric acid and the resulting white precipitate was filtered and dried to give 29.5 g. (90 percent yield) of product which melted at '-140 C. The 29.0 g. (0.17 mole) of acid prepared in step (a) was suspended in 1,500 ml. of water and 90 ml. of 2N sodium hydroxide (0.18 mole) was added with stirring. After the acid had dissolved, ml. of 1N hydrochloric acid was added. The resulting precipitate was filtered and dried to give 20 g. of trans- 1,1a,6,6a-tetrahydro-1H-cycloprop[a]i ndenecarboxylic acid. Repeated crystallization from benzene gave 1 1.5 g. of the trans isomer which melted at Analysis: Calculated for C,,H,,0,; C,75.S4; H,5.'79

Found C,76.26; H.589

c. The acidic filtrate from step (b) was treated with 50 ml. of 1N hydrochloric acid and the resulting precipitate was filtered and dried to yield 8 g. of cis-l ,1a,6,6a-tetrahydrm 1H-cycloproplalindenecarboxylic acid. Crystallization from chloroform gave 4.5 g. of the Cis-isomer which melted at 161-163 C.

Analysis: Calculated for C H,,O,:

Found C,75.84; H,5.79 C,75.44; H,5.8O

Preparation 2 Analysis: Calculated for C l-L 0 Found C',76.57; H.642 C,76.67; H,6.5l

The second crystalline fraction, cis-la,2,3,7b-tetrahydro-1 H-cyclopropa[a]naphthalenecarboxylic acid weighed 7.6 g. and melted at 161163 C. following crystallization from benzene-petroleum ether (30-60 G). Nuclear magnetic resonance confirmed the designated configurations.

Analysis: Calculated for C 11, 0

Found C,76.57; H,6.42 C,76.64; H.656

Preparation 3 trans- 1-(4-Phenyll -piperazinylcarbonyl l a,2,3,7btetrahydro- 1 H-cyclopropa[ a naphthalene.

A solution of 3 g. (0.016 mole) of trans-la,2,3,7btetrahydrol H-cyclopropa[a]naphthalenecarboxylic acid and 4 ml. of thionyl chloride was stirred at room temperature 18 hours. The excess thionyl chloride was removed in vacuo. To the resulting acid chloride, dissolved in ml. of dry benzene, was added dropwise, with stirring, 2.58 g. (0.016 mole) of 4- phenylpiperazine in 40 ml. of dry benzene. The reaction mixture was stirred two hours at room temperature, treated with 50 ml. of 1.5N sodium hydroxide solution and stirred minutes. The heterogeneous mixture was filtered and the precipitate was washed with water. The filtrate was separated and the benzene layer was dried over magnesium sulfate. The solid precipitate and the benzene filtrate were combined and treated with warm isooctane. On cooling, 4.2 g. (80 percent) of amide crystallized and melted at 193-l 94 C.

Analysis:

Calculated for C H N O: C,79.48; H,7.28; N,8,43 Found C,79.28; H,7.24; N,8.75

Preparation 4 cisl -(4-Phenyll -piperazinylcarbonyl l a,2,3,7btetrahydro-1l-l-cyclopropa[a]naphthalene.

A mixture of 2.4 g. (0.013 mole) of cis-la,2,3,7btetrahydrol Hcyclopropa[a]naphthalenecarboxylic acid, 2.64 g. (0.013 mole) of dicyclohexylcarbodiimide and 2.1 g. (0.013 mole) of 4-phenylpiperazine in 30 ml. of methylene chloride was stirred at room temperature 4 hours. The insoluble urea was filtered off and the filtrate was acid-base extracted. The organic layer was dried over magnesium sulfate and concentrated to an oil in vacuo. Crystallization of the crude oil from ethanol-water gave 2.5 g. (59 percent yield) of product which melted at l24l26 C- Analysis:

Calculated for C H N oz C,79.48; H,7.28; N,8.43 Found C,79.28; H.732; N,8.63

reacting cisl a,2,3,7b-tetrahydrol H-cyclopropa[a]n aphthalenecarboxylic acid, 4-phenylpiperidine and dicyclohexylcarbodiimide;

cis-l-[4-(4 tolyl)-1,2,3 ,G-tetrahydrol pyridinylcarbonyl la2,3 ,7b-tetrahydrol H-cyclopropa[a]naphthalene is prepared by reacting cis-la,2,3,7b-tetrahydro-1H- cyclopropa[a]naphthalene-carboxylic acid, 4-(4-tolyl)- l ,2,3,6-tetrahydropyridine and dicyclohexylcarbodiimide;

cis l -[4-( 4-anisyl l ,2,3,6-tetrahydrol -pyridinylcarbonyl]-1 l a,6,6a-tetrahydrol H-cycloprop[a]indene is prepared reacting cisl l a,6,6a-tetrahydro-l H-cycloprop[a]i ndenecarboxylic acid, 4-(4-anisyl)-l ,2,3,6-tetrahydropyridine and dicyclohexylcarbodiimide;

6 cisl-[ 3-(2-anisyl)- l-pyrrolidinylcarbonyl1- l a,2,3 ,7btetrahydrol H-cylopropa[a]naphthalene is prepared by reacting cis- 1a,2,3 ,7btetrahydrol H-cyclopropa[ a]n aphthalenecarboxylic acid, 3-(2-anisyl)pyrrolidine and dicyclohexylcarbodiimide;

cisl 4-( 2-ethoxyphenyl 1-piperidinylcarbonyl1- l a,2,3,7b-tetrahydrol H-cyc|opropa[alnaphthalene is prepared by reacting cisl a,2,3 ,7b-tetrahydrol H- cyclopropa[a]naphthalenecarboxylic acid, 4-(2-ethoxyphenyl )piperidine and dicyclohexylcarbodiimide;

cisl (4-benzyll -piperidinylcarbonyl l la,6,6atetrahydro-lH-cycloprop[a]indene is prepared by reacting cisl 1a,6,6a-tetrahydrol H-cycloprop[a]indenecarboxylic acid, 4-benzylpiperidine and dicyclohexylcarbodiimide;

cis- 1-[4-(4-chlorophenyl)- 1 -piperazinylcarbonyl l,la,6,6a-tetrahydro-1H-cycloprop[a lindene is prepared by reacting cisl la,6,6a-tetrahydrol H-cycloprop[a]indenecarboxylic acid, 4(4-chlorophenyl)piperazine and dicyclohexylcarbodiimide.

Preparation 5 Trans- 1 -(4-phenyll -piperazinylcarbonyl l 1a,6,6atetrahydro-lH-cycloprop[a]indene.

A mixture of 6.5 g. (0.04 mole) of l ,la,6,6a-tetrahydro-1H- cycloprop[a]indenecarboxylic acid and 20 ml. of thionyl chloride was stirred at room temperature for 18 hours, and the excess thionyl chloride was removed in vacuo. The residual acid chloride was dissolved in 20 ml. of chloroform and added dropwise, with stirring, to a mixture containing 6.05 g. (0.04 mole) of 4-phenylpiperazine dissolved in 20 ml. of chloroform, 10 g. of potassium carbonate and 25 ml. of crushed ice. When the reaction mixture reached room temperature, the chloroform layer was separated, dried over magnesium sulfate and concentrated to a semi-solid. Crystallization of the crude residue from benzene gave 9.2 g. percent) of product which melted at 187-l 89 C.

Analysis:

Calculated for C H N O: (1,7921; H,6.96; N,8.80 Found C,79.l7; H,6.93; N,8.57

By following the manipulative procedure of Preparation 5 the following intermediates are prepared:

Preparation 6 Trans-l-[4-(4-anisyl)-l-piperazinylcarbonyll-1a,2,3,7btetrahydrol H-cyclopropa[ a] naphthalene.

The acid chloride obtained from 4 g. (0.02 mole) of transla,2,3,7b-tetrahydrol H-cyclopropa[a]naphthalenecarboxylic acid was reacted with 5.6 g. (0.02 mole) of 4-(4- anisyl)piperam'ne dihydrochloride. The resulting product was crystallized from benzene-isooctane, melted at l65-l67 C. and weighed 6.2 g. (76% yield).

Analysis: Calculated for CgaHmNgOg: C,76.2 l; H,7.23; N,7.73 Found C,75.98; H,7.26; N,7.60

Preparation 7 Trans- 1 -[4 4-chl0rophenyl l ,2,3,6-tetrahydrol -pyridinyl-carbonyl]- l a,2,3,7b-tetrahydrol H-cyclopropa[a ]naphthalene.

The acid chloride obtained from 6 g. (0.032 mole) of transla,2,3 ,7b-tetrahydrol H-cyclopropa[aJnaphthalenecarboxylic acid was reacted with 7.4 g. (0.032 mole) of 4-(4- chlorophenyl l ,2,3,6-tetrahydropyridine hydrochloride. The resulting product was crystallize from isopropyl ether, melted at l54-156 C. and weighed 9.5 g. (82 percent yield).

Analysis: Calculated for C H ClNO: C,75.9l; H609; N,3.85

Found C,75.95; H,6.09; N,3.98

Preparation 8 Trans- 1 4-benzyll -piperidinylcarbonyl l a,2,3,7b-tetrahydrol H-cyclopropa[ a]naphthalene.

The acid chloride obtained from 6 g. (0.032 mole) of transa,2,3 ,7B-tetrahydrol H-cyclopropa[a]naphthalenecarboxylic acid was reacted with 5.6 g. (0.032 mole) of 4-benzylpiperidine. The resulting product was crystallized from isopropyl ether, melted at l20-l22 C. and weighed 8.2 g. (75 percent yield). 7

Analysis:

Calculated for C H NO: C,83.43; 11.7.88; N,4.05 C,83.38; H,7.96; N,4. 10

Found Preparation 9 Analysis:

Calculated for C H NO: C,83.85; H.104; N,4.25 Found C,8 3.78; H.704; N,4.35

Utilizing the procedures of Preparations 5 through 9, the following intermediates are prepared by reacting equimolar amounts of the stated ingredients:

transl -[4-( 3-trifluoromethylphenyl l -piperidinylcarbonyl l a,2,3 ,7b-tetrahydrol H-cyclopropa[a]naphthalene is prepared from transl a,2,3,7b-tetrahydrol H-cyclopropala] n aphthalenecarbonyl chloride and 4-( 3-tn'fluoromethylphenyl)piperidine;

transl 4-( 4-anisyl l -piperidinylcarbonyl l ,1a,6,6atetrahydro-ll-l-cycloprop[a]indene is prepared from transl 1a,6,6a-tetrahydro-l H-cycloprop[ a]indenecarbonyl chloride and 4-(4-anisyl)piperidine;

transl 3-phenyll-pyrrolidinylcarbonyl l a,2,3,7btetrahydro-lH cycl0propa[a]naphthalene is prepared from transl a, 2,3 -,7b-tetrahydrol H-cyclopropa[ a]naphthalenecarbonyl chloride and 3-phenylpyrrolidine;

transl-[ 3-( 4-ethoxyphenyl l 3-pyrrolinyl )carbonyl l a, 2,3,7b-tetrahydro-lH-cyclopropa{a]naphthalene is prepared from trans- I a,2,3 ,7b-tetrahydrol H-cyclopropa[a 1n aphthalene carbonyl chloride and 3-(4-ethoxyphenyl)-3-pyrroline;

transl -[4-(4-fluorophenyi l ,2,3,6-tetrahydro- 1 -pyridinylcarbonyl l l a,6,6a-tetrahydrol Hcycloprop[a]indene is prepared from transl l a,6,6a-tetrahydrol H-cycloprop[a]i ndenecarbonyl chloride and 4-(4-fluorophenyl)-l,2,3,6- tetrahydropyridine;

trans-l -(4-benzyll-piperidinylcarbonyl)-l la,6,6atetrahydro-lH-cycloprop[a]indene is prepared from transl l a,6,6a-tetrahydrol H-cycloprop[ a]indenecarbonyl chloride and 4-benzyl-piperidine;

trans-l 3-phenyll 3-pyrrolinyl )carbonyl l l a,6,6atetrahydro-lH-cycloprop[a]indene is prepared from transl l a,6,6a-tetrahydrol H-cycloprop[ ajindenecarbonyl chloride and 3-phenyl-3-pyrroline;

trans- 1 3-( 3-tolyl l -pyrrolidinylcarbonyl 1-1 l a,6,6atetrahydro-lH-cycloprop[a]indene is prepared from transl l a,6, 6a-tetrahydro- 1H-cycloprop[a]indenecarbonyl chloride and 3-( 3-tolyl)pyrr0lidine.

The examples below illustrate in detail some of the compounds which comprise this invention and methods for their production. This invention contemplates the cis and trans isomers as well as mixturesof cis and trans isomers. This invention is not to be construed as limited thereby in spirit or scope. it will be apparent to one skilled in the an that numerous modifications in materials and methods can be adopted without departing from the invention.

EXAMPLE 1 Transl 4-Phenyll -piperazinylmethyl l a.2,3 ,7btetrahydrol H-cyclopropa{ alnaphthalene.

A suspension of 3.7 g. (0.012 mole) of trans-l-(4-phenyll piperazinylcarbonyl l a,2,3,7b-tetrahydrol H- cyclopropalalnaphthalene in 100 ml. of anhydrous ether was added dropwise, under nitrogen, to a stirred suspension of l g. (0.026 mole) of lithium aluminum hydride in 50 ml. of ether. The mixture was refluxed 3 hours, cooled and treated with water saturated with magnesium sulfate. The inorganic salts were filtered and washed with ether. The combined ether fractions were concentrated to an oil. The residual oil was crystallized from ethanol water to give 3.5 g. (89 percent) of product which melted at 8992 C. The analytical sample was recrystallized from ethanol-water and melted at 90-92 C.

Analysis: Calculated for C H N C3297; H,8.23

Found C,83.08; H,8.34

EXAMPLE 2 I Transl 4-Phenyll -piperazinylmethyl )-l la,6,6a-tetrahydrol H-cycloprop[a]indene Hydrochloride Hydrate.

To a stirred suspension of 1.86 g. (0.049 mole) of lithium aluminum hydride in 50 ml. of anhydrous ether, under nitrogen, was added dropwise a suspension of 7.8 g. (0.0245 mole) of transl 4-phenyll-piperazinylcarbonyl l l ,a,6,6atetrahydro-lH-cycloprop[a]indene in 200 ml. of ether. The mixture was refluxed 3 hours, the excess lithium aluminum hydride was decomposed by the addition of 2 ml. of water, 2 ml. of 5N sodium hydroxide solution and60 ml. of water. The mixture was filtered and the filtrate was dried over magnesium sulfate and concentrated to an oil. The crude oil was converted to the hydrochloride salt which was crystallized from methanol-isopropyl ether, weighed 7.7 g. (88 percent) andmelted at 247248 C. with decomposition.

Analysis: Calculated for C- .,H, N,OCI: C,70.27; H,7.58; N.7.8l Found Utilizing the procedure of Examples 1 and 2, the following compounds are prepared:

EXAMPLE 3 Trans- 1 4-( 4-chlorophenyl )-l ,2,3,6-tetrahydrol pyridinyl-methyl l a,2,3,7b-tetrahydrol H-cyclopropa[a ]naphthalene Hydrochloride.

A suspension of 8.l g. (0.0273 mole) of trans-l-[4-(4- chlorophenyl l ,2,3,6-tetrahydrol -pyn'dinylcarbonyl l a,2,3,7b-tetrahydrol H-cyclopropa[a]naphthalene was reduced using 1.74 g. (0.045 mole) of lithium aluminum hydride. The crude product was converted to the hydrochloride salt which was crystallized from isopropanolisopropyl ether, weighed 7 g. (67 percent yield) and melted at 2 l 2-2l5 C. with decomposition.

Analysis: Calculated for C H NCl Found EXAMPLE 4 Cisl 4-phenyil-piperazinylmethyl)- la,2,3,7btetrahydrolH-cyclopropa[a]naphthalene,

A suspension of 2.2 g. (0.0067 mole) of cis-l-(4-phenyl-l piperazinylcarbonyl l a,2,3,7b-tetrahydrol H-cyclopropa a] naphthalene was reduced using 0.49 g. (0.013 mole) of lithium aluminum hydride. The product was crystallized from methanol-water, weighed 1.95 g. (91% yield) and melted at 7 l-74 C.

Analysis:

Calculated for CnHggNg: Found EXAMPLE Trans-1-(4-Benzy1-l-piperidinylmethyl)-1a,2,3,7btetrahydro- 1 H-cyclopropa[a]naphthalene Hydrochloride.

A suspension of 6.9 g. (0.02 mole) of trans-1-(4-benzyl-lpiperidinylcarbonyl)-1a,2,3,7b-tetrahydro-1H- cyclopropa[a]naphthalene was reduced using 1.52 g. (0.04 mole) of lithium aluminum hydride. The crude product was convened to the hydro-chloride salt which was crystallized from isopropanol-isopropyl ether, weighed 6.2 g. (84 percent yield) and melted at 179182 C.

Analysis:

Calculated for C H NClz C,78.34; H,8.22; N,3.8l Found C,77.90; H, .23;N,3.76

EXAMPLE 6 Trans-1-[4-(4-Anisyl)-1-piperazinylmethy1]-1a,2,3,7btetrahydrol H-cyclopropa[a] naphthalene Hydrochloride.

A suspension of 5 g. (0.013 mole) trans-1-[4-(4-anisyD-1- piperazinylcarbonyl1- 1 a,2,3 ,7b-tetrahydro-1H- cyclopropa[a]naphthalene was reduced using 1.1 g. (0.029 mole) of lithium aluminum hydride. The product was converted to the hydrochloride salt which was crystallized from isopropanol-isopropyl ether, weighed 5 g. (100 percent yield) and melted at 200 C. with decomposition.

Analysis: Calculated for C H N OC1: C,71.76; H,7.59; N,7.28 Found C,71.20; H753; N724 EXAMPLE 7 trans-1-(4-Phenyl-1 ,2,3 ,-tetrahydro-1-pyridiny1methyl)- l a,2,3,7b-tetrahydro- 1 H-cyclopropa[a]naphthalene Hydrochloride l-lemihydrate.

A suspension of 6.3 g. (0.019 mole) of trans-1-(4-phenyl- 1 ,2,3,6-tetrahydro-1-pyridiny1carbony1)-1a,2,3,7btetrahydro-lH-cyclopropa[a]naphthalene was reduced using 1.46 g. (0.038 mole) of lithium aluminum hydride. The crude product was converted to the hydrochloride salt which was.

crystallized from isopropanol-isopropyl ether, weighed 5.3 g. (79 percent yield) and melted at 219221 C. with decomposition.

Analysis: Calculated for C H N Cl O: C,76.54; H,7.54; N,3.88 Found :C,76.86; H.731; N,3.85

EXAMPLE 8 cisl -[4-(4tolyl l ,2,3,6-tetrahydro-* 1 -pyridinylmethyl 1 a, 2,3,7b-tetrahydro-ll-l-cyclopropa[a]naphthalene is prepared by reduction of cis-l-[4-(4-tolyl)-l,2,3,6-tetrahydro-1-pyridinyl-carbonyl} 1 a,2,3,7b-tetrahydrol H-cyclopropa[ a] naphthalene;

cis- 1 -[4-( 4-anisyl)- l ,2,3,6-tetrahydro- 1 -pyridinylmethyl l,la,6,6a-tetrahydrolH-cycloprop[a]indene is prepared by reduction of cis-1-[4-(4-anisy1)-l ,2,3,6-tetrahydrol -pyridinyl-carbony1]-1 1a,6,6a:tetrahydro- 1 Hcycloprop[a]indene;

cis-1-[3-(2-anisy1)-l-pyrrolidinylmethyl]-1a,2,3-7btetrahydro-lH-cyc1opropa[a]naphthalene is prepared by reduction of cis-1-[3-.(2-anisyl)-l-pyrrolidinylcarbonyl]- 1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene;

cis-1-[4-(2 -e thoxyphenyl)-1-pipeiidinylmethyl]-1a,2,3 ,7btetrahydro-lH-cyclopropa[a naphthalene is prepared by reduction ,of cis- 1-[4( 2-ethoxyphenyl l piperidinylcarbonyl]-1a,2,3,7b-tetrahydro-l H-cyclopropa[a]naphtha1ene;

cis-1-(4-benzyl- 1 -piperidinylmethyl )-l l a,6,6a-tetrahydro- 1H-cycloprop[a]indene is prepared by reduction of cis-1-(4- benzyl 1 -piperidinylca.rbonyl l 1 a,6,6a-tetrahydro- 1 H- cycloprop[a]indene;

cis- 1-[4-(4-chlorophenyl)- 1-piperazinylmethy1]- 1 l a,6,6a'- tetrahydro- 1 H-cycloprop[a indene is prepared by reduction of cis- 1 -[.4-(4-chlorophenyl l-piperazinylcarbonyl1- 1 l a,6,6atetrahydro- 1 H-cycloprop[ a]indene;

trans-l-[4-(4- anisyl)-1-piperidinylmethyl]-l,1a,6,6atetrahydro-lH-cycloprop[a]indene is prepared by reduction of trans-l-[4-(4 anisy1)-1piperidinylcarbonyu-l,1a,6,6atetrahydrol H cycloprop[ a ]indene;

trans-1-[4-(3-trifluoromethylphenyl)- 1 -piperidinylmethyl 1a,2,3 ,7b-tetrahydro1H-cyclopropa[a]napthalene is prepared by reduction of trans-l-[4-(3-trifluoromethylphenyl)-l-piperidinyl-carbony1]-1a,2,3,7b-tetrahydro-1H- cyclopropa[a]naphthalene;

transl 3-phenyl-1-pyrrolidinylmethyl)-1a,2-,3 ,7b-

tetrahydro-1H-cyclopropa[a]naphthalene is prepared by reduction of trans-1-( 3-phenyl-l-pyrrolidinylcarbonyl)- 1 a,2,3,7b-tetrahydro- 1 H-cyclopropa[a]naphthalene;

trans-1-[3-(4-ethoxyphenyl)- l-(3-pyrrolinyl)methyl]-1a, 2,3,7b-t etrahydro-lH-cyclopropa[a]naphthalene is prepared by reduction of transl -[3-(4-ethoxyphenyl)- l 3-pyrroliny1)carbony1]- 1 a,2,3,7b-,tetrahydro- 1 l-l-cyclopropa[a] naphthalene;

transl 4-( 4-fluorophenyl l ,2,3,6-tetrahydro- 1 -pyridinylmethyl} 1 1a,6,6a-,tetrahydrd l H-cycloprop[a]indene is prepared by reduction of trans-1-[4-(4-fluorophenyl)-l ,2,3,6- tetrahydro-1-pyridiny1carbonyl]- 1 1a,6,6a-tetrahydr0- 1 H- cycloprop[a]indene;

transl 4-benzyl- 1 -piperidiny1methyl 1 1a,6,6a-' tetrahydro-1H-cycloprop[a]indene is prepared by reduction of trans-1-(4-benzyl-l-piperidinylcarbonyl)- l ,1a,6,6atetrahydro-1H-cycloprop[a]indene;

trans-1-[3-phenyl-l-(3-pyrroliny1)methyl]-1,1a,6,6atetrahydro-1H-cyc1oprop[a]indene is prepared by reduction of trans-1-[3-phenyl-1-(3-pyrro1inyl)carbonyl]-l ,1a,6,6atetrahydro- 1 H-cycloprop[ a]indene;

trans-1 3-( 3-tolyl)- l-pyrrolidinylmethy1]- l ,1a,6,6atetrahydro-lH-cycloprop[a]indene is prepared by reduction of trans- 1-[ 3-( 3-toly1)- 1-pyrrolidiny1carbonyl1- l 1a,6,6atetrahydrol H-cycloprop[a]indene.

FORMULATION AND ADMINISTRATION The present invention also contemplates novel compositions containing the compounds of the invention as active ingredients. ln forming the novel compositions of this invention, the active ingredient is incorporated in a suitable carrier, illustratively, a pharmaceutical carrier. Suitable pharmaceutical carriers which are useful in formulating the tablet of this invention include starch, gelatin, glucose, magnesium carbonate, lactose, malt and the like. Liquid compositions are also within the purview of this invention and suitable liquid pharmaceutical carriers include ethyl alcohol, water, saline,

' physical form of the novel compositions depends in part upon the physical characteristics of the active ingredient. When the active ingredient is a solid, the composition is preferably forthe wet mass through an eight mesh screen. The wet granulation is dried and sized through a twelve mesh screen. The dried granules are blended with the calcium stearate and compressed.

l d as a capsule or table when the ti e i gredi m i a Additional tablet formulations preferably contain a higher liquid, the composition is preferably formulated as a soft dosage of the active ingredient and are as follows! gelatin capsule. The preferred composition is a table contain- A 50 8- Table ing the active ingredient in the form of its non-toxic acid addition salt. Ingredients Per Tablet, mg.

Although small quantities of the active materials of the w present invention are effective when minor therapy is involved Agti e ingredient as n 50 o or in cases of administration to subjects having a relatively low La to 90.0 body weight, unit dosages are usually 5 milligrams or above 3'8 and preferably 25, 50 or 100 milligrams or even higher, de- I 5 calcium Steam, pending, of course, upon the emergency of the situation and Total 200.0 mg. the particular result desired. Five to 100 milligrams appear to be optimum per unit dose, while usual broader ranges appear to be one to 500 milligrams P unit dose h is y necessary Uniformly blend the active ingredient, lastose, milo starch that the active ingredient constitute an effective amount, re, d h om tarch. This blend is granulated using water as a such that a suitable effective dosage will be obtained conulatin medium. The wet granules are passed through an sistent with the age f m emp oy b y. Several ni eight mesh screen and dried at 140 to 160 F over night. The dosage forms may be administered at about the same time. dri d a ul are as ed through a number 10 e h gr The following are example of Comp iti n f me i and blended with the proper amount of calcium stearate and cordance with this invention. this blend is then converted into tablets on a suitable tablet 1. Capsules press. Capsules of 5 mg., 25 mg., and 50 mg. of active ingredient B. 100 mg. Tablet per capsule are prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose. Ingredients Per Tablet, mg.

. Typical Blend for Encapsulation Per Capsule, mg. Active ingredient as S3 [000 Lactose 190.0 Active ingredient, as salt 5.0 g i fi phosphate Lactose 296-7 Milo starch 21.6 Starch v 290 Calcium stearate 2.2 Magnesium stearate 4.3 5400 mg Total 435.0 mg. U a

mformly blend the active ingredient, lactose, dicalcium phosphate, starch and mil starch. This blend is granulated with water and the wet mass is passed through a number eight mesh Additional capsule formations preferably contain a higher 40 screen. The wet granules are dried at l40-l60 F over night. dosage of active ingredient and are as follows: The dried granules are passed through a number 10 mesh screen. These dried granules are blended with the proper 100 mg. per 250 mg. per 500 mg. per weight of calcium stearate and the lubricated granules are Ingredients Capsule Capsule Capsule then converted into tablets on a suitable tablet press.

3. Intramuscular in jection Active ingredient, as salt 100.0 250.0 500.0 Ingredients P r l Lactose 231.5 I 126.5 31.1 Starch 99.2 54.2 13.4 Magnesium stearate 4.3 4.3 5.5 59 Active Ingredient 500 Total 3 0 4350 Q 0 2. isotonic buffer solution, 4.0: q.s. to 2.0 ml.

in each case, uniformly blend the selected active ingredient procequre t with lactose, Starch and magnesium steam: and encapsulate 55 l. Dissolve the active ingredient in the buffer solution. the blemi 2. Aseptically filter the solution from step l.

2 Tablets 3. The sterile solution is now aseptically filled into sterile A typical formulation for a tablet containing 5.0 mg. of acampoulestive ingredient per tablet follows. The formulation may be 4'The ampoules are Sealed under aseptic used for other strengths of active ingredient by adjustment of 60 syrup weight of dicalcium phosphate.

Ingredients Amts./5 cc.

Per Tablet, mg.

1. Active ingredient 100.0000 mg. h 2. Glycerin 1.2500 m1. l. Active ingredient. as salt 59 3. Sorbitol solution 2.5000 ml. 2. Corn starch 4. Sodium saccharin 1.0000 mg. 3. Corn starch (paste) 5. Sodium sucaryl 10.0000 mg. 4. Lactose 792 6. Methyl p-aminobenzoate 5.0000 mg. 5. Dicalcium phosphate 7. Propyl p-aminobenzoate 0.2500 mg. 6. Calcium stearate 7O 8. Curacao flavor 0.0025 ml. Total 170.1 mg- 9. Water q.s. 5.0000 ml.

Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 per cent Procedure l. Dissolve 6 and 7 in hot water.

paste in water. Granulate the blend with starch paste and pass 2. This solution, when cool, is mixed with No. 3 and the mixture is stirred until uniform.

3. Dissolve 1, 2, 4, 5 and 8 in this solution and stir until uniform.

Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, compositions, methods, and procedures of the present invention without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.

What is claimed is:

1. A compound selected from (a) cis and trans isomers of heterocyclic bases having the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, trifluoromethyl and halogen of atomic weight less than eighty,

n is a positive integer from l to 2 inclusive, and (b) acid addition salts thereof.

2. The compound as defined in claim 1, which is trans-l-( 4- phenyll -piperazinylmethyl l a,2,3,7b-tetrahydrol H- cyclopropa[a]naphthalene.

3. The compound as defined in claim 1, which is trans-l-[4- (4-anisyl)- l-piperazinylmethyl]- la,2,3,7b-tetrahydro-1H- cyclopropa[a]naphthalene.

4. The compound as defined in claim 1, which is transl-(4- phenyll -pipera.zinylmethyl )-l ,la,6,6a-tetrahydro-1H- cycloprop[a]indene.

5. The compound as defined in claim 1, which is cisl-(4- phenyll -piperazinylmethyl l a,2,3,7b-tetrahydrol H- cyclopropa[a]naphthalene.

6. A process for the preparation of heterocyclic bases having the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, trifluoromethyl and halogen of atomic weightless than 80, and

n is a positive integer from 1 to 2 inclusive, which comprises the steps of: i l. reacting a carboxylic acid selected from the group consisting of l l a,6,6a-tetrahydrol H-cycloprop[a]i ndenecarboxylic acid and la,2,3,7b-tetrahydro-lI-lcyclopropa[a]naphthalenecarboxylic acid with a thionyl halide; 2. reacting the acyl halide prepared in a step (1) with a 4- phenylpiperazine having the formula wherein R is as defined above to mula give an amide having the forwherein n and R are as defined above.

3. reducing the amide from step (2) with lithium aluminum hydride to produce the trans isomers of compounds having the formula wherein R is as defined above to formula @WCTQNQR give a cis amide having the (CH2) n wherein n and R are as defined above.

* II k UNITED STATES ?ATENT OFFICE CETIFICATE UF CORRECTION Patent No. 5, 666,761 D d May 30, 1972 l v fl William John Welstead, Jr.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 13, lines 1 to 18, the formula should appear as shown below instead of as in the patent:

R Q CH N N 2)n Column 15, lines 38 to M2, the formula should appear as shown below instead of as in the patent:

R v Q Signed and sealed this 26th day of September 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR ROBERT GOTTSCHAL n a K Attesting Officer Commissioner of Patents PRM PC9-1050 (10-69) USCOMM-DC 60376-5 69 u.s. eovzauuzur rnmmlc dmc: Ian 0-0-334 

2. The compound as defined in claim 1, which is trans-1-(4-phenyl-1-piperazinylmethyl)-1a,2,3,7b-tetrahydro-1H -cyclopropa(a)naphthalene.
 2. reacting the acyl halide prepared in a step (1) with a 4-phenylpiperazine having the formula wherein R is as defined above to give an amide having the formula wherein n and R are as defined above.
 3. reducing the amide from step (2) with lithium aluminum hydride to produce the trans isomers of compounds having the formula wherein n and R are as defined above.
 3. The compound as defined in claim 1, which is trans-1-(4-(4-anisyl)-1-piperazinylmethyl)-1a,2,3,7b-tetrahydro-1H -cyclopropa(a)naphthalene.
 4. The compound as defined in claim 1, which is trans-1-(4-phenyl-1-piperazinylmethyl)-1,1a,6,6a-teTrahydro-1H -cycloprop(a)indene.
 4. reacting a cis carboxylic acid of step (1) with equimolar amounts of dicyclohexylcarbodiimide and a 4-phenylpiperazine having the formula wherein R is as defined above to give a cis amide having the formula wherein n and R are as defined above.
 5. reducing the cis amide prepared in step (4) with lithium aluminum hydride to produce the cis isomers having the formula wherein n and R are as defined above.
 5. The compound as defined in claim 1, which is cis-1-(4-phenyl-1-piperazinylmethyl)-1a,2,3,7b-tetrahydro-1H -cyclopropa(a)naphthalene.
 6. A process for the preparation of heterocyclic bases having the formula: wherein R is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, trifluoromethyl and halogen of atomic weight less than 80, and n is a positive integer from 1 to 2 inclusive, which comprises the steps of: 